Caveolin-1 upregulation contributes to c-Myc-induced high-grade prostatic intraepithelial neoplasia and prostate cancer

Guang Yang, Alexei A. Goltsov, Chengzhen Ren, Shinji Kurosaka, Kohei Edamura, Richard Logothetis, Francesco J. DeMayo, Patricia Troncoso, Jorge Blando, John DiGiovanni, Timothy C. Thompson

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Abstract

Previously we reported caveolin-1 (Cav-1) overexpression in prostate cancer cells and showed that it promotes prostate cancer progression. Here, we report that Cav-1 was overexpressed in 41.7% (15 of 36) of human highgrade prostatic intraepithelial neoplasia (HGPIN) specimens obtained during radical prostatectomies. Positive correlations exist between Cav-1-positive (Cav-1 +) HGPIN and Cav-1 + primary prostate cancer (rho = 0.655, P < 0.0001) and between Cav-1 and c-Myc expression in HGPIN (rho = 0.41, P = 0.032). To determine whether Cav-1 cooperates with c-Myc in development of premalignant lesions and prostate cancer in vivo, we generated transgenic mice with c-Myc overexpression driven by the ARR 2PB promoter. In this ARR 2PB-c-myc model, Cav-1 overexpression was found in mouse PIN (mPIN) lesions and prostate cancer cells and was associated with a significantly higher ratio of proliferative to apoptotic labeling in mPIN lesions than in the Cav-1-negative epithelia adjacent to those lesions (10.02 vs. 4.34; P = 0.007). Cav-1 overexpression was also associated with increased levels of P-Akt and VEGF-A, which were previously associated with Cav-1-induced prostate cancer cell survival and positive feedback regulation of cellular Cav-1 levels, respectively. In multiple prostate cancer cell lines, Cav-1 protein (but not mRNA) was induced by c-Myc transfection, whereas VEGF siRNA transfection abrogated c-Myc-induced Cav-1 overexpression, suggesting a c-Myc-VEGF-Cav-1 signaling axis. Overall, our results suggest that Cav-1 is associated with c-Myc in the development of HGPIN and prostate cancer. Furthermore, Cav-1 overexpression in HGPIN is potentially a biomarker for early identification of patients who tend to develop Cav-1 + primary prostate cancer.

Original languageEnglish
Pages (from-to)218-229
Number of pages12
JournalMolecular Cancer Research
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 1 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Yang, G., Goltsov, A. A., Ren, C., Kurosaka, S., Edamura, K., Logothetis, R., DeMayo, F. J., Troncoso, P., Blando, J., DiGiovanni, J., & Thompson, T. C. (2012). Caveolin-1 upregulation contributes to c-Myc-induced high-grade prostatic intraepithelial neoplasia and prostate cancer. Molecular Cancer Research, 10(2), 218-229. https://doi.org/10.1158/1541-7786.MCR-11-0451